The present invention relates to methods for monitoring the effectiveness of tamoxifen (2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine) therapy in the treatment of breast cancer, and more particularly to methods of detecting the emergence of tamoxifen-resistant tumors and the resulting treatment resistance by means of an analytical assay for antiestrogenic and other forms of tamoxifen and its metabolites.
Breast cancer is the most common form of malignant disease among women of the Western world, and it is the most common cause of death among those between 40 and 45 years of age. This disease will develop in about six to seven percent of women in the United States, and at the present time about one half of this group can be cured. The treatment of breast cancer involves surgery, radiation, chemotherapeutics and hormonal therapy, the last category including consideration of antiestrogens for treatment of endocrine-responsive tumors.
Tumors sensitive to estrogen stimulation may regress following competitive inhibition of estrogen receptors by tamoxifen (an antiestrogen), and response is currently predicted based on the stage of disease and on the basis of assays for estrogen receptors (ER) and progesterone receptors (PR) in the tissue. Many breast cancers and all normal estrogen-responsive tissues contain these labile cytoplasmic proteins which bind estrogen and progesterone. Patients with positive assays for these proteins have an objective response to hormone therapy of about 65%, while those with negative assays have an objective response rate of &lt;10%. For postmenopausal women having a first recurrence of breast cancer with an ER+ or PR+ assay, tamoxifen therapy is the treatment of choice.
Notwithstanding strong interest in the use of antiestrogens in breast cancer treatment, however, incomplete knowledge of their basic pharmacology persists. Substituted triphenylethylenes (including tamoxifen) have antiestrogen effects which appear to be dependent on geometric isomerism. For example, trans-tamoxifen (the isomer used in tamoxifen therapy) is an antiestrogen, whereas the cis isomer is a weak estrogen. The present invention makes use of newly acquired knowledge about in vivo interconversion of geometric isomers to improve treatment of breast cancer.
Although tamoxifen is the most widely used antiestrogen for treating breast cancer, development of tamoxifen resistance and subsequent tumor progression during tamoxifen therapy represents a major reason for treatment failures. The mechanism of tamoxifen resistance has been unknown, but an estrogenic metabolite of tamoxifen which would promote growth in ER+ tamoxifen-resistant tumors has been identified.